For over one hundred years, scientists have observed spatial preferences for the organization of the chromosomes within the nucleus. While we have now deciphered the entire genome sequences of eukaryotic species from yeasts to humans, how those genomes are physically organized to support genomic functions remains an open question. Within the last few years, several studies in yeast and mammalian models have suggested that association of genes with the nuclear periphery, likely with inner nuclear membrane proteins, acts to regulate transcription. The importance of these studies is underscored by the discovery that several human diseases are associated with mutations within integral inner nuclear membrane proteins including emerin, which causes Emery-Dreifuss Muscular Dystrophy (EDMD). Treatment strategies are extremely challenging to devise, however, since there remains substantial confusion over two key issues of how the nuclear periphery influences transcription: 1) in yeast, association with the nuclear periphery appears to activate some genes while repressing others, and 2) it remains controversial whether heterologously driving a reporter gene to the periphery is sufficient to induce transcriptional repression in mammalian cells. In this proposal, our strategy is to derive genome-wide maps of chromatin-inner nuclear membrane interactions in two yeast models, S. cerevisiae and S. pombe (Aim 1). These organisms display correspondence of 80% of their protein coding genes while lacking significant synteny; we can leverage these properties to identify genes (and the regulatory pathways they contribute to) with conserved sites for inner nuclear membrane association, which we predict will reflect functional importance. In Aim 2, we will examine how regulatory stimuli alter the association of genes with the nuclear periphery, assess the requirement for specific inner nuclear membrane proteins in the regulation of these genes, and test the ability of engineered and reversible tethers to recapitulate gene regulation at the nuclear periphery. Our long-term goal is to understand how we might ameliorate the changes in the transcriptome that result from mutations in inner nuclear membrane proteins, and establish paradigms to allow us to devise strategies to tackle a growing number of genetic diseases including EDMD, which are collectively called nuclear envelopathies.